The endoplasmic reticulum–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B cell development in mice
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Author
Yang, YiKong, Sinyi
Zhang, Yana
Melo-Cardenas, Johanna
Gao, Beixue
Zhang, Yusi
Zhang, Donna D.
Zhang, Bin
Song, Jianxun
Thorp, Edward
Zhang, Kezhong
Zhang, Jinping
Fang, Deyu
Affiliation
Univ Arizona, Dept Pharmacol & ToxicolIssue Date
2018-08-17
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Yang, Yi & Kong, Sinyi & Zhang, Yana & Melo-Cardenas, Johanna & Gao, Beixue & Zhang, Yusi & D. Zhang, Donna & Zhang, Bin & Song, Jianxun & Thorp, Edward & Zhang, Kezhong & Zhang, Jinping & Fang, Deyu. (2018). The endoplasmic reticulum-–resident E3 ubiquitin ligase Hrd1 controls a critical checkpoint in B- cell development in mice. Journal of Biological Chemistry. 293. jbc.RA117.001267. 10.1074/jbc.RA117.001267.Journal
JOURNAL OF BIOLOGICAL CHEMISTRYRights
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Humoral immunity involves multiple checkpoints that occur in B cell development, maturation, and activation. The pre-B-cell receptor (pre-BCR) is expressed following the productive recombination of the immunoglobulin heavy-chain gene, and sSignalsing through the pre-BCR are required for the differentiation of pre-B cells into immature B cells. However, the molecular mechanisms controlling the pre-BCR expression and signaling strength remain undefined. Herein, we probed the role of the endoplasmic reticulum-associated, stress-activated E3 ubiquitin ligase HMG-CoA reductase degradation 1 (Hrd1) in B cell differentiation. Using mice with a specific Hrd1 deletion in pro-B cells and subsequent B cell developmental stages, we showed that the E3 ubiquitin ligase Hrd1 governs a critical checkpoint during B cell development. We observed that Hrd1 is required for degradation of the pre-BCR complex during the early stage of B cell development. As a consequence, loss of Hrd1 in the B cell lineage resulted in increased pre-BCR expression levels and a developmental defect in the transition from large to small pre-B cells. This defect, in turn, resulted in reduced fewer mature B cells in bone marrow and peripheral lymphoid organs. Our results revealed a novel critical role of Hrd1 in controlling a critical checkpoint in B cell-mediated immunity and suggest that Hrd1 may functioning as an E3 ubiquitin ligase of the pre-BCR complex.Note
12 month embargo; published online: 15 June 2018ISSN
0021-92581083-351X
PubMed ID
29907570Version
Final published versionSponsors
National Institutes of Health [AI079056, AI108634, AR006634]; National Natural Science Foundation of China (NSFC) [81600784, 31270939, 81471526, 81771667]; Training Program of the Major Research Plan in regional immunology of the National Natural Science Foundation of China [91442110]; Natural Science Foundation of Jiangsu Province [BK20170349]; postdoctoral foundation of China; Social development project of Jiangsu Province Grant [BE2016676]; Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences of Soochow UniversityAdditional Links
http://www.jbc.org/lookup/doi/10.1074/jbc.RA117.001267ae974a485f413a2113503eed53cd6c53
10.1074/jbc.RA117.001267
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